Cardiovascular Effects of Secondhand Smoke Nearly as Large as Those of Smoking—and How about Renal Effects?
Authors: Barnoya J., Glantz S.A.
Journal: Journal of the American Society of Nephrology (2006)

One of the most remarkable achievements of nephrology in recent decades was the observation that progression of renal disease is susceptible to intervention. Although the efficacy of intervention, particularly by lowering blood pressure (1) and by blockade of the renin-angiotensin system (2–4), has been proven in controlled trials, the long-term outcomes are not fully satisfactory (5). The answer may well be the combination of different types of intervention (6), a strategy that has been immensely successful in diabetes (7). A complementary approach is the elimination of additional insults to the kidney, e.g., cessation of smoking (8), avoidance of nonsteroidal anti-inflammatory agents (9) or of acetaminophen, aspirin, and other analgesics (10)—although harm by the latter agents has not been universally confirmed. In diabetic patients, the adverse renal effects of smoking were observed 27 years ago (11) and observational studies suggested that cessation of smoking attenuated the progression of diabetic nephropathy (12). These observations in diabetic patients went largely unnoticed by the renal community, however, until solid evidence was provided by a retrospective case-control study which showed that the risk of end-stage renal disease in nondiabetic patients with primary renal diseases (i.e., IgA glomerulonephritis or polycystic renal disease) was significantly higher in smokers, at least in male smokers (13). More recently, several studies confirmed this finding (14,15) and some authors documented deterioration of renal function even in patients without primary renal disease, e.g., severe hypertension (16), advanced age (17) and others. A high proportion of smokers is found among microalbuminuric subjects (18–20) and a prospective study in the general population found that current cigarette smoking increased the relative risk of chronic kidney disease (CKD) by a factor of 2.9 in women and 2.4 in men. Cigarette smoking accounted for 31% of the attributable risk of CKD (21). Because of these and other data, it has been recommended that individuals with CKD should be strongly advised to stop smoking (8). But is this good enough? The above scholarly paper by Barnoya and Glantz (22) marshals the evidence that the effect of passive smoking on cardiovascular risk is surprisingly strong and quantitatively comes close to that of active smoking. Some background information on passive smoking may be useful. Great concern about health hazards from passive smoking had originally been raised by the study of Hirayama (23), who had noted an excess frequency of bronchial carcinoma in nonsmoking Japanese wives married to smoking husbands. This finding helped create awareness that environmental tobacco smoke can harm nonsmokers (24). This finding is hardly surprising: Not only the mainstream smoke, which is inhaled and exhaled by the smoker, but also the sidestream smoke contains numerous substances (actually >4000 substances in sidestream smoke, of which 50 are known carcinogens) (25). The composition differs from mainstream smoke and is in some respects even more alarming (26). The main forms of passive exposure to smoke are the working place, the home and—somewhat less important quantitatively—restaurants/bars and public transportation (27). As recently described in detail by Diethelm et al., the high risk of sidestream smoke had apparently been known to the industry, particularly Philip Morris USA, for a long time (26). To conceal access to the primary experimental data, a sophisticated structure of secret transfer of experimental data had been arranged and what had been published was apparently manipulated by industry (28). There is not only clear evidence in the meta-analysis of Boffetta (29) that individuals exposed to passive smoke more frequently have bronchial carcinoma with a relative risk of 1.25 (95% confidence interval [CI] 1.15 to 1.37). The authors also found a definite dose-response relationship, the odds ratio for the highest exposure group being 2.8 (1.6 to 4.8) (30). But apart from these known risks of carcinoma and pulmonary disease, there is now also incontrovertible evidence for a high cardiovascular risk of passive smoking as summarized in the above meta-analysis of Barnoya (22), which included the results of 29 studies. Using a random effects model, the author computed the pooled relative risk of ischemic heart disease: In never smokers exposed to second-hand smoke relative to the risk in individuals not exposed to second-hand smoke, the risk estimate was 1.31 (95% CI 1.21 to 1.41)—more than one would expect, based on the known risk associated with active smoking and the relative doses of tobacco smoke delivered to smokers and nonsmokers. For several reasons this observation is bad news for renal patients. First, even minor renal dysfunction causes a dramatic increase of cardiovascular risk (31–33) and for obvious reasons any additional risk is most undesirable. Second, however, the suspected pathomechanisms by which passive smoking causes vascular lesions and raises cardiovascular risk are likely to play a role in the genesis of the predominantly vascular lesions underlying progression of renal disease in smokers. Although studies on the acute effects of smoking in occasional smokers with renal disease found an acute increase in albumin excretion (34), histological evaluation of renal biopsies in patients with primary renal disease showed evidence of pronounced vascular lesions in smokers compared to nonsmokers, i.e., significantly more marked myointimal hyperplasia and a trend for more severe arteriolar lesions (35). This observation is in line with functional studies in chronic smokers, which documented reduced renal plasma flow despite maintained GFR, accompanied by increased plasma endothelin concentrations as putative evidence of endothelial cell dysfunction (14). What is the evidence for platelet activation, endothelial dysfunction, oxidative stress, and inflammation by second-hand smoke? As soon as 20 minutes after exposure of nonsmokers to second-hand smoke, platelets were activated to the point that they were no longer discernibly different from platelets of smokers (36). This observation is in line with the study of Rubenstein et al. (37): Extracts from sidestream smoke activated platelets more potently than extracts from mainstream smoke. Furthermore, thromboxane and other markers of platelet activation are significantly increased in passive smokers (38). Evidence of endothelial cell dysfunction is provided by observations that, within minutes after exposure to second-hand smoke, endothelium-dependent vasodilatation (39) and coronary flow reserve (40) are reduced. This is accompanied by decreased endothelial nitric oxide (41). Second-hand smoke causes oxidative stress (42) and leads to antioxidant depletion such as decreased vitamin C (43), β-carotene (44), and folate (45) concentrations. This is accompanied by increased plasma 8-hydroxy-2-deoxyguanosine concentrations (46) as evidence of oxidant DNA damage and by a compensatory increase in enzymes breaking down reactive oxidant species such as superoxide dismutase or glutathione peroxidase. Finally, the evidence of inflammation triggered by second-hand smoke comprises increased acute phase proteins (47), fibrinogen (48), activation of neutrophils (49), and others. The obvious question raised by the above findings is this: Should we advise renal patients not only to stop smoking but also to try to avoid passive exposure to cigarette smoke? Although none of the textbooks mentions this, I think the answer should be yes and I hope that the above arguments convince other nephrologists as well.